Role for substance p-based nociceptive signaling in progenitor cell activation and angiogenesis during ischemia in mice and in human subjects

Our data highlight the role of SP in reparative neovascularization. Nociceptive signaling may represent a novel target of regenerative medicine.

Targeting stem cell niches and trafficking for cardiovascular therapy.

Regenerative cardiovascular medicine is the frontline of 21st-century health care. Cell therapy trials using bone marrow progenitor cells documented that the approach is feasible, safe and potentially beneficial in patients with ischemic disease. However, cardiovascular prevention and rehabilitation strategies should aim to conserve the pristine healing capacity of a healthy organism as well as reactivate it under disease conditions. This requires an increased understanding of stem cell microenvironment and trafficking mechanisms. Engagement and disengagement of stem cells of the osteoblastic niche is a dynamic process, finely tuned to allow low amounts of cells move out of the bone marrow and into the circulation on a regular basis. The balance is altered under stress situations, like tissue injury or ischemia, leading to remarkably increased cell egression. Individual populations of circulating progenitor cells could give rise to mature tissue cells (e.g. endothelial cells or cardiomyocytes), while the majority may differentiate to leukocytes, affecting the environment of homing sites in a paracrine way, e.g. promoting endothelial survival, proliferation and function, as well as attenuating or enhancing inflammation. This review focuses on the dynamics of the stem cell niche in healthy and disease conditions and on therapeutic means to direct stem cell/progenitor cell mobilization and recruitment into improved tissue repair.

Cigarette smoke-induced neurogenic inflammation is mediated by α,β-unsaturated aldehydes and the TRPA1 receptor in rodents

Cigarette smoke (CS) inhalation causes an early inflammatory response in rodent airways by stimulating capsaicin-sensitive sensory neurons that express transient receptor potential cation channel, subfamily V, member 1 (TRPV1) through an unknown mechanism that does not involve TRPV1. We hypothesized that 2 alpha,beta-unsaturated aldehydes present in CS, crotonaldehyde and acrolein, induce neurogenic inflammation by stimulating TRPA1, an excitatory ion channel coexpressed with TRPV1 on capsaicin-sensitive nociceptors. We found that CS aqueous extract (CSE), crotonaldehyde, and acrolein mobilized Ca2+ in cultured guinea pig jugular ganglia neurons and promoted contraction of isolated guinea pig bronchi. These responses were abolished by a TRPA1-selective antagonist and by the aldehyde scavenger glutathione but not by the TRPV1 antagonist capsazepine or by ROS scavengers. Treatment with CSE or aldehydes increased Ca2+ influx in TRPA1-transfected cells, but not in control HEK293 cells, and promoted neuropeptide release from isolated guinea pig airway tissue. Furthermore, the effect of CSE and aldehydes on Ca2+ influx in dorsal root ganglion neurons was abolished in TRPA1-deficient mice. These data identify alpha,beta-unsaturated aldehydes as the main causative agents in CS that via TRPA1 stimulation mediate airway neurogenic inflammation and suggest a role for TRPA1 in the pathogenesis of CS-induced diseases.

The Met Office unified model global atmosphere 4.0 and JULES global land 4.0 configurations

We describe Global Atmosphere 4.0 (GA4.0) and Global Land 4.0 (GL4.0): configurations of the Met Office Unified Model and JULES (Joint UK Land Environment Simulator) community land surface model developed for use in global and regional climate research and weather prediction activities. GA4.0 and GL4.0 are based on the previous GA3.0 and GL3.0 configurations, with the inclusion of developments made by the Met Office and its collaborators during its annual development cycle. This paper provides a comprehensive technical and scientific description of GA4.0 and GL4.0 as well as details of how these differ from their predecessors. We also present the results of some initial evaluations of their performance. Overall, performance is comparable with that of GA3.0/GL3.0; the updated configurations include improvements to the science of several parametrisation schemes, however, and will form a baseline for further ongoing development.

The mirror neuron system as revealed through neonatal imitation: presence from birth, predictive power, and evidence of plasticity

There is strong evidence that neonates imitate previously unseen behaviors. These behaviors are predominantly used in social interactions, demonstrating neonates’ ability and motivation to engage with others. Research on neonatal imitation can provide a wealth of information about the early mirror neuron system (MNS): namely, its functional characteristics, its plasticity from birth, and its relation to skills later in development. Though numerous studies document the existence of neonatal imitation in the laboratory, little is known about its natural occurrence during parent-infant interactions and its plasticity as a consequence of experience. We review these critical aspects of imitation, which we argue are necessary for understanding the early action-perception system. We address common criticisms and misunderstandings about neonatal imitation and discuss methodological differences among studies. Recent work reveals that individual differences in neonatal imitation positively correlate with later social, cognitive, and motor development. We propose that such variation in neonatal imitation could reflect important individual differences of the MNS. Although postnatal experience is not necessary for imitation, we present evidence that neonatal imitation is influenced by experience in the first week of life.

Northern winter climate change: assessment of uncertainty in CMIP5 projections related to stratosphere–troposphere coupling

Future changes in the stratospheric circulation could have an important impact on Northern winter tropospheric climate change, given that sea level pressure (SLP) responds not only to tropospheric circulation variations but also to vertically coherent variations in troposphere-stratosphere circulation. Here we assess Northern winter stratospheric change and its potential to influence surface climate change in the Coupled Model Intercomparison Project – phase 5 (CMIP5) multi-model ensemble. In the stratosphere at high latitudes, an easterly change in zonally averaged zonal wind is found for the majority of the CMIP5 models, under the Representative Concentration Pathway 8.5 scenario. Comparable results are also found in the 1% CO2 increase per year projections, indicating that the stratospheric easterly change is common feature in future climate projections. This stratospheric wind change, however, shows a significant spread among the models. By using linear regression, we quantify the impact of tropical upper troposphere warming, polar amplification and the stratospheric wind change on SLP. We find that the inter-model spread in stratospheric wind change contributes substantially to the inter-model spread in Arctic SLP change. The role of the stratosphere in determining part of the spread in SLP change is supported by the fact that the SLP change lags the stratospheric zonally averaged wind change. Taken together, these findings provide further support for the importance of simulating the coupling between the stratosphere and the troposphere, to narrow the uncertainty in the future projection of tropospheric circulation changes.

Changes in global net radiative imbalance 1985-2012

Combining satellite data, atmospheric reanalyses and climate model simulations, variability in the net downward radiative flux imbalance at the top of Earth's atmosphere (N) is reconstructed and linked to recent climate change. Over the 1985-1999 period mean N (0.34 ± 0.67 Wm–2) is lower than for the 2000-2012 period (0.62 ± 0.43 Wm–2, uncertainties at 90% confidence level) despite the slower rate of surface temperature rise since 2000. While the precise magnitude of N remains uncertain, the reconstruction captures interannual variability which is dominated by the eruption of Mt. Pinatubo in 1991 and the El Niño Southern Oscillation. Monthly deseasonalized interannual variability in N generated by an ensemble of 9 climate model simulations using prescribed sea surface temperature and radiative forcings and from the satellite-based reconstruction is significantly correlated (r ∼ 0.6) over the 1985-2012 period.

Simulation of the global ENSO–Tropical cyclone teleconnection by a high-resolution coupled general circulation model

This study assesses the influence of the El Niño–Southern Oscillation (ENSO) on global tropical cyclone activity using a 150-yr-long integration with a high-resolution coupled atmosphere–ocean general circulation model [High-Resolution Global Environmental Model (HiGEM); with N144 resolution: ~90 km in the atmosphere and ~40 km in the ocean]. Tropical cyclone activity is compared to an atmosphere-only simulation using the atmospheric component of HiGEM (HiGAM). Observations of tropical cyclones in the International Best Track Archive for Climate Stewardship (IBTrACS) and tropical cyclones identified in the Interim ECMWF Re-Analysis (ERA-Interim) are used to validate the models. Composite anomalies of tropical cyclone activity in El Niño and La Niña years are used. HiGEM is able to capture the shift in tropical cyclone locations to ENSO in the Pacific and Indian Oceans. However, HiGEM does not capture the expected ENSO–tropical cyclone teleconnection in the North Atlantic. HiGAM shows more skill in simulating the global ENSO–tropical cyclone teleconnection; however, variability in the Pacific is overpronounced. HiGAM is able to capture the ENSO–tropical cyclone teleconnection in the North Atlantic more accurately than HiGEM. An investigation into the large-scale environmental conditions, known to influence tropical cyclone activity, is used to further understand the response of tropical cyclone activity to ENSO in the North Atlantic and western North Pacific. The vertical wind shear response over the Caribbean is not captured in HiGEM compared to HiGAM and ERA-Interim. Biases in the mean ascent at 500 hPa in HiGEM remain in HiGAM over the western North Pacific; however, a more realistic low-level vorticity in HiGAM results in a more accurate ENSO–tropical cyclone teleconnection.

Investigating hydrological regimes and processes in a set of catchments with temporary waters in Mediterranean Europe

Seven catchments of diverse size in Mediterranean Europe were investigated in order to understand the main aspects of their hydrological functioning. The methods included the analysis of daily and monthly precipitation, monthly potential evapotranspiration rates, flow duration curves, rainfall runoff relationships and catchment internal data for the smaller and more instrumented catchments. The results showed that the catchments were less dry than initially considered. Only one of them was really semi-arid throughout the year. All the remaining catchments showed wet seasons when precipitation exceeded potential evapotrans-piration, allowing aquifer recharge, wet runoff generation mechanisms and relevant baseflow contribution. Nevertheless, local infiltration excess (Hortonian) overland flow was inferred during summer storms in some catchments and urban overland flow in some others. The roles of karstic groundwater, human disturbance and low winter temperatures were identified as having an important impact on the hydrological regime in some of the catchments.

Challenges in quantifying changes in the global water cycle

Understanding observed changes to the global water cycle is key to predicting future climate changes and their impacts. While many datasets document crucial variables such as precipitation, ocean salinity, runoff, and humidity, most are uncertain for determining long-term changes. In situ networks provide long time-series over land but are sparse in many regions, particularly the tropics. Satellite and reanalysis datasets provide global coverage, but their long-term stability is lacking. However, comparisons of changes among related variables can give insights into the robustness of observed changes. For example, ocean salinity, interpreted with an understanding of ocean processes, can help cross-validate precipitation. Observational evidence for human influences on the water cycle is emerging, but uncertainties resulting from internal variability and observational errors are too large to determine whether the observed and simulated changes are consistent. Improvements to the in situ and satellite observing networks that monitor the changing water cycle are required, yet continued data coverage is threatened by funding reductions. Uncertainty both in the role of anthropogenic aerosols, and due to large climate variability presently limits confidence in attribution of observed changes.

Tropical cyclones in the UPSCALE ensemble of high resolution global climate models

The UPSCALE (UK on PRACE: weather-resolving Simulations of Climate for globAL Environmental risk) project, using PRACE (Partnership for Advanced Computing in Europe) resources, constructed and ran an ensemble of atmosphere-only global climate model simulations, using the Met Office Unified Model GA3 configuration. Each simulation is 27 years in length for both the present climate and an end-of-century future climate, at resolutions of N96 (130 km), N216 (60 km) and N512 (25 km), in order to study the impact of model resolution on high impact climate features such as tropical cyclones. Increased model resolution is found to improve the simulated frequency of explicitly tracked tropical cyclones, and correlations of interannual variability in the North Atlantic and North West Pacific lie between 0.6 and 0.75. Improvements in the deficit of genesis in the eastern North Atlantic as resolution increases appear to be related to the representation of African Easterly Waves and the African Easterly Jet. However, the intensity of the modelled tropical cyclones as measured by 10 m wind speed remain weak, and there is no indication of convergence over this range of resolutions. In the future climate ensemble, there is a reduction of 50% in the frequency of Southern Hemisphere tropical cyclones, while in the Northern Hemisphere there is a reduction in the North Atlantic, and a shift in the Pacific with peak intensities becoming more common in the Central Pacific. There is also a change in tropical cyclone intensities, with the future climate having fewer weak storms and proportionally more stronger storms

Characteristics of tropical cyclones in high-resolution models in the present climate

The global characteristics of tropical cyclones (TCs) simulated by several climate models are analyzed and compared with observations. The global climate models were forced by the same sea surface temperature (SST) fields in two types of experiments, using climatological SST and interannually varying SST. TC tracks and intensities are derived from each model's output fields by the group who ran that model, using their own preferred tracking scheme; the study considers the combination of model and tracking scheme as a single modeling system, and compares the properties derived from the different systems. Overall, the observed geographic distribution of global TC frequency was reasonably well reproduced. As expected, with the exception of one model, intensities of the simulated TC were lower than in observations, to a degree that varies considerably across models.

Hurricanes and climate: the U.S. CLIVAR working group on hurricanes

While a quantitative climate theory of tropical cyclone formation remains elusive, considerable progress has been made recently in our ability to simulate tropical cyclone climatologies and understand the relationship between climate and tropical cyclone formation. Climate models are now able to simulate a realistic rate of global tropical cyclone formation, although simulation of the Atlantic tropical cyclone climatology remains challenging unless horizontal resolutions finer than 50 km are employed. This article summarizes published research from the idealized experiments of the Hurricane Working Group of U.S. CLIVAR (CLImate VARiability and predictability of the ocean-atmosphere system). This work, combined with results from other model simulations, has strengthened relationships between tropical cyclone formation rates and climate variables such as mid-tropospheric vertical velocity, with decreased climatological vertical velocities leading to decreased tropical cyclone formation. Systematic differences are shown between experiments in which only sea surface temperature is increased versus experiments where only atmospheric carbon dioxide is increased, with the carbon dioxide experiments more likely to demonstrate the decrease in tropical cyclone numbers previously shown to be a common response of climate models in a warmer climate. Experiments where the two effects are combined also show decreases in numbers, but these tend to be less for models that demonstrate a strong tropical cyclone response to increased sea surface temperatures. Further experiments are proposed that may improve our understanding of the relationship between climate and tropical cyclone formation, including experiments with two-way interaction between the ocean and the atmosphere and variations in atmospheric aerosols.

Phosphorescence quantum yield enhanced by intermolecular hydrogen bonds in Cu4I4 clusters in the solid state

Organo-copper(I) halide complexes with a Cu4I4 cubane core and cyclic amines as ligands have been synthesized and their crystal structures have been defined. Their solid state photophysical properties have been measured and correlated with the crystal structure and packing. A unique and remarkably high luminescence quantum yield (76%) has been measured for one of the complexes having the cubane clusters arranged in a columnar structure and held together by N–HI hydrogen bonds. This high luminescence quantum yield is correlated with a slow radiationless deactivation rate of the excited state and suggests a rather strong enhancement of the cubane core rigidity bestowed by the hydrogen bond pattern. Some preliminary thin film deposition experiments show that these compounds could be considered to be good candidates for applications in electroluminescent devices because of their bright luminescence, low cost and relatively easy synthesis processes

Standardized evaluation of algorithms for computer-aided diagnosis of dementia based on structural MRI: The CADDementia challenge

Algorithms for computer-aided diagnosis of dementia based on structural MRI have demonstrated high performance in the literature, but are difficult to compare as different data sets and methodology were used for evaluation. In addition, it is unclear how the algorithms would perform on previously unseen data, and thus, how they would perform in clinical practice when there is no real opportunity to adapt the algorithm to the data at hand. To address these comparability, generalizability and clinical applicability issues, we organized a grand challenge that aimed to objectively compare algorithms based on a clinically representative multi-center data set. Using clinical practice as the starting point, the goal was to reproduce the clinical diagnosis. Therefore, we evaluated algorithms for multi-class classification of three diagnostic groups: patients with probable Alzheimer's disease, patients with mild cognitive impairment and healthy controls. The diagnosis based on clinical criteria was used as reference standard, as it was the best available reference despite its known limitations. For evaluation, a previously unseen test set was used consisting of 354 T1-weighted MRI scans with the diagnoses blinded. Fifteen research teams participated with a total of 29 algorithms. The algorithms were trained on a small training set (n = 30) and optionally on data from other sources (e.g., the Alzheimer's Disease Neuroimaging Initiative, the Australian Imaging Biomarkers and Lifestyle flagship study of aging). The best performing algorithm yielded an accuracy of 63.0% and an area under the receiver-operating-characteristic curve (AUC) of 78.8%. In general, the best performances were achieved using feature extraction based on voxel-based morphometry or a combination of features that included volume, cortical thickness, shape and intensity. The challenge is open for new submissions via the web-based framework: http://caddementia.grand-challenge.org.